The premise behind this grant application is that impeccable characterization and understanding of a systemically administered new antineoplastic agent's pharmacology and effect on molecular targets in cancer should allow better clinical utilization of that agent. Determination of clinical toxicities and maximum tolerated dose (MTD) of an agent is no longer sufficient. Ideally, early clinical trials of an investigational agent should define pharmacokinetic (PK) disposition and metabolism, with correlation to pharmacodynamic (PD) manifestations at molecular, cellular, and clinical levels. With this abiding philosophy and hypothesis, performance of scientifically directed phase I trials of promising novel anti-cancer agents available through the National Cancer Institute is warranted. Integrating information regarding the mechanism of action and effect on molecular targets with development of biomarkers in phase I trials is the strategy that will be pursued with the following objectives to : define the toxicities of new antineoplastic agents in patients with advanced cancer; re-define (as necessary)the toxicities and PK of existing anticancer agents administered in combination with molecularly targeted agents, colony stimulating factors and other toxicity-ameliorating agents that may facilitate the exploration of more effective doses and schedules; provide information on the absorption, distribution, metabolism, and elimination of antitumor agents; define treatment regimens for use in phase II trials; establish, based on clinical and pharmacologic characteristics, appropriate phase II doses in special patient populations (e.g., patients with impaired organ function; heavily pretreated patients or geriatric patient populations), explore PK and PD differences based on sex, race, or ethnic group; obtain preliminary information on PK/PD correlations that can then be extended in phase II trials; incorporate basic laboratory and correlative science studies, when possible and appropriate, to enhance the understanding of the biochemical and/or biological mechanisms of drug actions; study the PK and the PD impact of drugs on specific metabolic pathways and molecular targets using non-invasive techniques such as magnetic resonance spectroscopy and nuclear imaging with radio-labeled drugs; and integrate pharmacogenomic studies to characterize differences in relevant drug metabolizing enzymes and drug targets related to toxicity and efficacy.